Vascular heterogeneity and specialization in development and disease.
Blood and lymphatic vessels pervade almost all body tissues and have numerous essential roles in physiology and disease. The inner lining of these networks is formed by a single layer of endothelial cells, which is specialized according to the needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vessel development are being defined with increasing molecular precision, studies of the processes of endothelial specialization remain mostly descriptive. Recent insights from genetic animal models illuminate how endothelial cells interact with each other and with their tissue environment, providing paradigms for vessel type- and organ-specific endothelial differentiation. Delineating these governing principles will be crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.


[Spontaneous pneumothorax and atmospheric pressure].
In order to assess factors associated with spontaneous pneumothorax (SP), mainly climatic changes, a prospective study was undertaken of 62 SP episodes among patients admitted to our hospital during a two-year period, from January 1994 to January 1996. Atmospheric pressure (AP) changes were analyzed, with daily recording of the number of unusual changes in AP (increases above 95th percentile and decreases below 5th percentile) and how many of these changes were followed by some episode of spontaneous pneumothorax during the following five days. To measure the degree of this association between the emergence of pneumothorax and exposure to unusual changes I AP, the relative risk (RR) was calculated. A total of 77 unusual AP changes were observed, 17 of which concurred with the emergence of 8 episodes of SP during the following five days, with a RR of 2.7 (1.6-4.4). Although the etiology of SP is unknown and probably of multifactorial origin, these data suggest that unusual changes in AP may play a relevant role in triggering this condition.


Early diagnosis of pancreatic adenocarcinoma: role of stroma, surface proteases, and glucose-homeostatic agents.
New-onset diabetes in pancreatic adenocarcinoma is due to a combination of insulin resistance and decreased β-cell function. Its differentiation from the common type 2 diabetes is the prerequisite for early diagnosis of pancreatic adenocarcinoma. Little attention has been paid to pancreatic stroma and surface proteases. The activated fibroblasts selectively express fibroblast activation protein α, a structural homolog of the ubiquitously expressed dipeptidyl peptidase 4. Their role in pancreatic carcinogenesis is reviewed. Homodimers and heterodimers of both enzymes display high specificity for peptides and proteins with penultimate proline or alanine. Most glucose-homeostatic agents are candidate substrates of these enzymes. The biological activity of truncated substrates is decreased or absent. The interactions of surface proteases with glucose-homeostatic agents may adequately explain the evolution of diabetes associated with pancreatic adenocarcinoma and differentiate it from the common type 2 diabetes.


Symmetrical lateralization of function in the auditory system of the cat: effects of unilateral ablation of cortex.
We have presented behavioral evidence suggesting that one function of auditory cortex is to attend to stimuli at the contralateral ear. Further, behavioral and anatomic evidence shows that the neural mechanisms for this function probably depend on a pathway that crosses at the level of the medulla, bypasses the superior olive, and ascends to the contralateral inferior colliculus. At higher centers there are several auditory pathways from thalamus to cortex, as well as descending pathways from cortex, and some of these pathways may play a role in selective listening with one ear.


Adjuvant systemic chemotherapy with gemcitabine for stage IV pancreatic cancer: a preliminary report of initial experience.
The effects of gemcitabine on postoperative adjuvant chemotherapy were evaluated in patients with stage IV pancreatic cancer. The results were compared with those of our historical control patients treated with surgery alone. Nineteen patients with stage IV pancreatic cancer who had pancreatic resection with curative intent during the 5 years up to February 2003 were enrolled in this study. Nine cases received postoperative adjuvant chemotherapy with biweekly administration of 1,000 mg/m(2) gemcitabine, while the remaining 10 cases underwent surgery without any adjuvant chemotherapy. The chemotherapy was well tolerated with only mild symptomatic and hematologic toxicities. The disease-specific cumulative survival rates of the chemotherapy and surgery-alone groups were 86 and 70% at 1 year, and 50 and 12% at 2 years, with a median survival of 20 and 14 months, respectively (p = 0.0255). The disease-free interval was improved, and the occurrence of hepatic metastasis was reduced in the chemotherapy group compared with the surgery-alone group. Adjuvant systemic chemotherapy utilizing gemcitabine was feasible with acceptable adverse effects, and showed some survival benefit in stage IV pancreatic cancer patients. Further investigation into gemcitabine-based combination therapies is warranted.


Role of protective drugs in the prevention of ulcer relapse.
The efficacy of gastric acid suppressive drugs, such as histamine H2-receptor antagonists and H+K+ ATPase inhibitors, in the management of peptic ulcer diseases has been well established. They accelerate the healing of peptic ulcers, and maintenance therapy with these drugs prevents ulcer relapse. However, they do not modulate the natural course of peptic ulcer. Sucralfate, a protective drug, has been shown to be equally effective in ulcer healing and the prevention of ulcer relapse. Some reports suggest that the relapse rate of ulcers treated successfully with sucralfate is less than that seen with histamine H2-receptor antagonists. Sucralfate has a true cytoprotective effect against agents noxious to gastric epithelial cells in monolayer culture. This action might be associated with its therapeutic efficacy in the treatment and prevention of ulcer diseases. The role played by other protective drugs in the management of ulcer diseases is less clear and requires further studies.


Catatonia in mixed alcohol and benzodiazepine withdrawal.
Catatonia is mostly caused by different neuropsychiatric conditions. We report a case of a 30 year old man suffering from both alcohol and benzodiazepine dependence who exhibited catatonic features soon after stopping the intake of substances. This case will help clinicians to recognize catatonic features within the varied symptomatology of substance withdrawal and thereby helping in its early diagnosis and management.


Preparation and evaluation of fluorescent poly(p-phenyleneethylene) covalently coated microspheres with reactive sites for bioconjugation.
Fluorescent microspheres with reactive sites for interacting with biomolecules are greatly demanded in flow cytometry based suspension array. Aiming to develop a new method for preparing fluorescent microspheres, two poly(p-phenyleneethylene) (PPE) conjugated polymers (CPs) with pedant carboxylic groups were synthesized via Sonogashira coupling and followed with hydrolysis of ester groups; then the conjugated polymers were immobilized onto monodispersed amino-modified porous poly(glycidylmethacrylate) (APGMA) microspheres via coupling reaction between carboxylic and amino groups to give APGMA-CP fluorescent microspheres. The fluorescent microspheres were found to have good photo- and thermal stability as well as negligible influence from rigorous washing. The emission was uniform all across the inner and surface of the spheres. To evaluate the effectiveness of bioconjugation on the fluorescent microspheres, fluorescein isothiocyanate isomer I (FITC) labeled bovine serum albumin (BSA) (BSA-FITC) was chosen as the representative biomolecule to react with the fluorescent microspheres to give APGMA-CP-BSA-FITC. In the flow cytometry study, fluorescence compensation between the V500 and FITC detectors (receiving signals from fluorophores excited by 405 nm and 488 nm, respectively), to remove the interference between the emission of FITC and CPs, was realized using singly-stained microspheres. Finally, APGMA-CP-BSA-FITC microspheres were found to be double positive for CP and FITC with very high percentage (>95%), suggesting the bioconjugation is very effective. This study provides a facile method for simultaneous introduction of fluorescence and reactive sites onto the microspheres, which is very promising to be used as general strategy for fabricating fluorescence microspheres for application in high-throughput technology.


Less Common Oral Diseases of Medical Significance.
The oral cavity is frequently involved in conditions that affect the skin or other multi-organ diseases. In many instances, oral involvement precedes the appearance of other symptoms or lesions at other locations. Anatomically, the mouth is easily accessible. An astute dental provider has the opportunity to observe physical and oral conditions that might include undiagnosed or poorly managed systemic disease. This article reviews four less common oral disease of medical significance.


Risk attribution and tobacco-related deaths.
The number of deaths that would not have occurred had an exposure or trait been absent is generally estimated by observing mortality rates in sample populations of exposed and nonexposed persons and applying them to the population of interest. Three methods used to estimate deaths due to tobacco use are evaluated. Each method requires estimates of certain absolute and relative risks, and the published estimates based on them assume that the absolute and relative risks observed in the two large American Cancer Society prospective studies can be applied to the US population or to populations in developed countries. Computations using large representative samples of US decedents and of the entire US population for these methods result in estimated numbers of deaths for the US population that are substantially lower than those based on Cancer Prevention Survey-I or Cancer Prevention Survey-II. Computations also showed that controlling for confounding from two smoking-related variables results in still lower estimates of the number of excess deaths. Consequently, published results that ignore confounding and are based on nonrepresentative data overstate the contribution of smoking. It is imperative that estimates of excess deaths be based on representative data and control for relevant confounders.


Purification and characterization of ribulose-1,5-bisphosphate carboxylase from triticale.
Ribulose-1,5-bisphosphate carboxylase has been isolated from a synthetic cereal triticale and purified using a newly developed rapid procedure involving precipitation with ammonium sulphate (35-55% saturation), DEAE-cellulose (DE-52) chromatography and filtration through Sepharose CL-68. Molecular weights of the enzyme subunits are 15.5 and 52 kDa which corresponds to 540 kDa for the hexadecameric holoenzyme. Isoelectric focussing showed that the enzyme has a pI of 4.2. Various kinetic constants determined under aerobic conditions are: Km (CO2), 118 microM; Km (RuBP), 220 microM (at 20 mM NaHCO3) and Vmax, 690 nmole CO2 fixed/mg enzyme/min.


Ecofriendly approach for detection of phenols in water using laccase from different fungi.
Laccase-initiated oxidative coupling reactions of phenol and its derivatives with 4-aminoantipyrene using air as an oxidant has been investigated. The oxidation reaction of phenols and 4-aminoantipyrene is getting a lot of attention due to environmental concerns. Oxidation of simple phenol and 4-aminoantipyrene as a benchmark reaction enabled us to rank the relative oxidation ability of various laccases. Among the laccases tested, laccase from Pycnoporus cinnabarinus successfully yielded 72% antipyrilquinoneimine dye. The present method can also be used to determine p-substituted phenols and chlorophenols. In this work, the influence of mediators on laccase activity has also been studied.


In silico functional profiling of small molecules and its applications.
In silico screening is routinely used in the drug discovery process to predict whether each molecule in a database has a function of interest, such as inhibitory activity for a target protein. However, drugs generally have multiple functions including adverse effects. In order to obtain small molecules with desirable physiological effects, it is useful to simultaneously predict as many functions as possible. We employed Support Vector Machine to build classification models for 125 molecular functions, derived from the MDDR database, which showed higher kappa statistics (0.775 on average) than those of predictions by Tanimoto similarity (0.708). By analyzing the patterns of the predicted values (functional profiles) of 871 marketed drugs, we demonstrated its applications to indication discovery, clustering of drugs, and detection of molecular actions related to adverse effects. The results showed that functional profiling can be a useful tool for identifying the multifunctionality or adverse effects of small molecules.


Dromyosuppressin and drosulfakinin, two structurally related Drosophila neuropeptides, are uniquely expressed in the adult central nervous system.
Drosophila myosuppressin (TDVDHVFLRFamide; DMS) and sulfakinin (FDDYGHMRFamide; DSK) have similar C-terminal structures. To determine the neuronal expression patterns of these structurally related peptides, we have generated DMS- and DSK-specific antisera to multiple antigenic peptides and performed double-label immunochemistry with antisera raised on different animals of the same species host animal. Our data indicate that DMS and DSK staining patterns in the adult central nervous system are unique and nonoverlapping.


Interventions to improve resilience in physicians who have completed training: A systematic review.
Resilience is a contextual phenomenon where a complex and dynamic interplay exists between individual, environmental, and socio-cultural factors. With growing interest in enhancing resilience in physicians, given their high risk for experiencing prolonged or intense stress, effective strategies are necessary to improve resilience and reduce negative outcomes including burnout. The objective of this review was to identify effective interventions to improve resilience in physicians who have completed training, working in any setting. We included randomized controlled trials (RCT), and observational studies (including pilot studies) published in English, French, and Spanish that included an intervention to improve resilience in physicians who have completed training. We included studies that implemented interventions to reduce burnout, anxiety, and depression or to improve empathy to ultimately enhance resilience, rather than studies designed solely to reduce stress or trauma-induced stress. We performed a systematic search of Medline, EMBASE, PsychInfo, CINAHL and Cochrane Library with no publication year limit. The last search was conducted on March 29, 2017. We used random effect models to calculate pooled standardized mean differences. Resilience was the primary outcome measure using validated resilience scores. Secondary outcome measures included proxy measures of resilience such as burnout, empathy, anxiety and depression. Our search strategy identified 7,579 records;74 met the criteria for full-text review. Seventeen studies were included in the final review published between 1998 and 2016 of which 9 (4 RCT, 5 observational) had physician data extractable. Interventions varied greatly regarding their approach, duration, and follow-up. Two RCTs measured resilience using validated scales; both found a significant improvement. No meta-analysis for resilience was conducted due to the presence of high clinical and methodological heterogeneity. Our systematic review demonstrates that there is weak evidence to support one intervention over another to improve resilience in physicians who have completed training. The quality of evidence for the outcomes ranged from very low to low. There is a need for a consensus on the definition of resilience and how it is measured. Longer follow-up is required to ensure any intervention effects are sustained over time.


Long-term clinical outcomes and economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy.
To examine long-term retention rate, clinical outcomes, cost-utility and cost-effectiveness of the Ketogenic Diet (KD) compared with care as usual (CAU) in children and adolescents with intractable epilepsy from a societal perspective. Participants were randomized into a KD or CAU group. Seizure frequency, quality adjusted life years (QALYs), side-effects, seizure severity, health care costs, production losses, patient and family costs were assessed at baseline and during 16-months of follow-up. Incremental cost-effectiveness ratios (ICERs) (i.e. cost per QALY and cost per responder) and cost-effectiveness acceptability curves are presented. 48 children were included in the analyses of this study (26 from KD group). In total, 58% of the KD group completed the follow-up of 16 months; 11 dropped-out for various reasons. At 16 months, 35% of the KD participants had a seizure reduction≥50% from baseline, compared with 18% of the CAU participants. Mean costs per patient in the CAU group were €53,367 (extrapolated) compared to €61,019 per patient in the KD group, resulting in an ICER of €46,564 per responder. Cost per QALY rose well above any acceptable ceiling ratio. At 4-months' follow-up, the KD group showed significantly more gastro-intestinal problems compared to the CAU group. At 16 months, the KD group reported fewer problems compared to CAU. Furthermore, 46.2% of the KD group reported a decrease in severity of their worst seizure compared to 32% of the CAU group. The KD group resulted in more responders and showed greater improvement on seizure severity. Furthermore, the KD did not lead to worsening of side-effects other than gastro-intestinal problems (only at 4 months' follow-up). However, as only a minimal difference in QALYs was found between the KD group and the CAU group, the resulting cost per QALY ratios were inconclusive.


Electroacupuncture up-regulates natural killer cell activity Identification of genes altering their expressions in electroacupuncture induced up-regulation of natural killer cell activity.
As an important cellular component of the innate immune system, NK cells constitute a first line of defense against various infections and malignancies. Previous studies have reported electroacupuncture (EA) modulation of natural killer cell (NK cell) activities. Our study confirmed that EA treatment increases NK cell activity using (51)Cr release assay. Furthermore, in order to better understand the activation mechanism of NK cell by EA, we employed a cDNA microarray technique to elucidate how EA alters gene expressions in the spleen of rats. We screened EA responsive genes using a high-throughput screening and identified 154 genes. Among those genes we selected 4 genes that are known to play a crucial role in NK cell activation and examined their mRNA expressions after EA treatment using RT-PCR. Our data shows that EA treatment increased CD94, PTK and VCAM-1 expressions while decreased PTP and SHP-1. These results imply that EA treatment increase PTK expression, which increases NK cell activity, through induction of CD94 while decreases SHP-1, which inhibits NK cell activity, simultaneously so that it activates NK cell with high efficacy. It seems that increased VCAM-1 expression is due to INF-gamma produced by activated NK cell. Increased production of VCAM-1 is expected to play an important role in binding of NK cell to the target cell. The result of our study may provide key insights in understanding the mechanisms of activation of NK cell induced by EA.


Ambulatory blood pressure measurement in type-II diabetic patients with autonomic neuropathy.
The aim of our study was to access the 24-hr ambulatory blood pressure (BP) in diabetic patients with autonomic neuropathy (AN). Twenty-two NIDDM patients without hypertension, being treated with sulfonylureas, were studied. The 24-hr ambulatory blood pressure recordings were performed using portable non-invasive automatic system. Autonomic neuropathy was assessed by standard cardiovascular reflex tests. There were ten patients with and 12 without AN, matched for age, body mass index, duration of diabetes and glycemic control. Mean BP increased at night in four of the subjects with AN and decreased in the remaining 18 patients. The group of subjects with nocturnal increases in BP had more severe autonomic nerve dysfunction compared with those with decreases in nocturnal BP. No significant difference between clinical and ambulatory day-time measurements was found. In three patients with AN after 5 weeks intensified therapy. 24-hr BP did not show any significant difference.


Mixed epithelial and stromal tumors of the kidney: evidence for a single cell of origin with capacity for epithelial and stromal differentiation.
Mixed epithelial and stromal tumors are uncommon biphasic tumors of the kidney, with cystic and solid areas composed of a morphologically diverse stroma, including ovarian-like stroma and an epithelial component with considerable heterogeneity. Little is known about the histogenesis and clonal origins of these tumors. A total of 21 mixed epithelial and stromal tumors of the kidney from female patients who underwent radical or partial nephrectomies were examined. The epithelial and stromal components, and also adjacent non-neoplastic renal parenchymal tissues were separately laser microdissected from sections prepared from formalin-fixed and paraffin-embedded tissues for X chromosome inactivation analysis. Nineteen of the 21 tumors were informative. Seven of these informative cases showed random X chromosome inactivation pattern in both epithelial and stromal components of mixed epithelial and stromal tumors of the kidney. Nonrandom inactivation of the X chromosome was found in 12 of 19 informative tumors. The same pattern of nonrandom inactivation of the X chromosome was seen in both epithelial and stromal components in all 12 of the tumors with nonrandom X chromosome inactivation. Our data support the theory that the stroma and epithelium arise from a common cell of origin.


Rapid multiorgan failure due to large B-cell lymphoma arising in human herpesvirus-8-associated multicentric Castleman's disease in a patient with human immunodeficiency virus infection.
A 46-year-old man presented with a high-grade fever, multiple lymphadenopathies, hepatosplenomegaly and human immunodeficiency virus (HIV) seropositivity, without severe immunosuppression. We suspected human herpesvirus-8 (HHV-8)-associated multicentric Castleman's disease (MCD) based on the results of a physical examination and laboratory investigations, including bone marrow aspiration. However, the patient died eight days after admission due to multiorgan failure. An autopsy revealed MCD and lymphoma cell infiltration in multiple organs. The final diagnosis was large B-cell lymphoma (LBCL) arising in HHV-8-associated MCD. This case illustrates the potential for LBCL in HHV-8 MCD in HIV-infected patients with hepatosplenomegaly and lymphadenopathy without severe immunosuppression and highlights the clinical significance of bone marrow aspiration.


Temperature dependent FCS studies using a long working distance objective: Viscosities of supercooled liquids and particle size.
In this work, we describe new experimental setups for Fluorescence Correlation Spectroscopy (FCS) where a long working distance objective is used. Using these setups, FCS measurements in a broad temperature range for a small sample volume of about 50 μl can be performed. The use of specially designed cells and a dry long working distance objective was essential for avoiding temperature gradients in the sample. The performance of the new setups and a traditional FCS setup with immersion objectives is compared. The FCS data in combination with the Stokes-Einstein (SE) relation were used to obtain the values of the nanoviscosity of a fluid. We show for selected molecular van der Waals supercooled liquids that despite the fact that in these systems, a characteristic length scale can be defined, the nanoviscosity obtained from FCS is in a very good agreement with the macroscopic (rheometric) viscosity of the sample in a broad temperature range. This result corroborates the applicability of the SE relation to supercooled liquids at temperatures above 1.2 Tg. We also show that the temperature dependent size of thermoresponsive microgel particles can be determined by FCS using the designed cells and a long working distance objective in a broader size range without a need to use the correction procedure since the size correction is proportional to the square of the ratio of the hydrodynamic radius to the confocal volume size.


Validation of liquid and gaseous calibration techniques for quantification of propofol in breath with sorbent tube Thermal Desorption System GC-MS.
Plasma concentrations of intravenous drugs cannot currently be evaluated in real time to guide clinical dosing. However, a system for estimating plasma concentration of the anesthetic propofol from exhaled breath may soon be available. Developing reliable calibration and analytical validation techniques is thus necessary. We therefore compared the established sorbent tube liquid injection technique with a gas injection procedure using a reference gas generator. We then quantified propofol with Tenax sorbent tubes in combination with gas-chromatography coupled mass spectrometry in the breath of 15 patients (101 measurements). Over the clinically relevant concentration range from 10 to 50 ppbv, coefficient of determination was 0.995 for gas calibration; and over the range from 10 to 100ng, coefficient of determination was 0.996 for liquid calibration. A regression comparing gas to liquid calibration had a coefficient of determination of 0.89; slope 1.05±0.01 (standard deviation). The limit of detection was 0.74ng and the lower limit of quantification was 1.12ng for liquid; the limit of detection was 0.90 ppbv and the lower limit of quantification was 1.36 ppbv for gas. Loaded sorbent tubes were stable for at least 14days without significant propofol loss as determined with either method. Measurements from liquid or gas samples were comparably suitable for evaluation of patient breath samples.


[Elevated liver enzymes of unknown etiology].
Elevated liver enzymes are a frequent clinical problem of varying significance. In otherwise healthy individuals the most frequent causes of elevated liver enzymes are toxins such as alcohol and drugs. In this situation, further studies are usually not needed; it is sufficient to control the relevant parameters after abstinence from alcohol or withdrawal of the drug(s). In patients with known, suspected or unknown nonhepatic diseases, elevated liver enzymes can be caused by cardiovascular diseases, obesity, endocrinopathies, infectious diseases, malignancies, collagen disorders, sarcoidosis and other diseases. In this situation, sonography or liver histology frequently will be diagnostic, revealing the cause of the underlying disease as well as of the elevated liver enzymes.


[Autologous blood replacement in urology].
In a total number of 67 urological operations (24 transurethral resections of the prostate, 30 transvesical resections of the prostate, 13 radical prostatectomies) intraoperative blood loss was saved, cleaned, and reinfused to the patients as washed, packed red blood cells with a "Cell Saver" (Haemonetics). Patients with preoperative urinary tract infection were excluded from reinfusion in transurethral resections of the prostate. Although radical prostatectomy is oncologic surgery we consider it an ideal possibility for intraoperative autotransfusion. Based on our experience, autotransfusion seems to be warranted also in urological surgery.


Bi-Deficiency Leading to High-Performance in Mg3 (Sb,Bi)2 -Based Thermoelectric Materials.
Mg3 (Sb,Bi)2 is a potential nearly-room temperature thermoelectric compound composed of earth-abundant elements. However, complex defect tuning and exceptional microstructural control are required. Prior studies have confirmed the detrimental effect of Mg vacancies (VMg ) in Mg3 (Sb,Bi)2 . This study proposes an approach to mitigating the negative scattering effect of VMg by Bi deficiency, synergistically modulating the electrical and thermal transport properties to enhance the thermoelectric performance. Positron annihilation spectrometry and Cs -corrected scanning transmission electron microscopy analyses indicated that the VMg tends to coalesce due to the introduced Bi vacancies (VBi ). The defects created by Bi deficiency effectively weaken the scattering of electrons from the intrinsic VMg and enhance phonon scattering. A peak zT of 1.82 at 773 K and high conversion efficiency of 11.3% at ∆T = 473 K are achieved in the optimized composition of Mg3 (Sb,Bi)2 by tuning the defect combination. This work demonstrates a feasible and effective approach to improving the performance of Mg3 (Sb,Bi)2 as an emerging thermoelectric material.


Mortality risk among tobacco users in a rural population of southern India: evidence from a cohort study.
Tobacco has long been identified as one of the most hazardous risk factors detrimental to health. To plan and implement anti-tobacco activities in any community, it is necessary to understand the risk it poses in that setting. We assessed the risk of mortality associated with tobacco use in a rural community of Kerala. This cohort study (PROLIFE) was done in Varkkala, a rural development block of Thiruvananthapuram district of Kerala. Adults aged 20 years and above were included. Age-adjusted mortality rates were computed for both users and non-users of tobacco. The risk of mortality was plotted using Kaplan-Meier curves. Cox regression was used to compute the age-adjusted hazard ratio of mortality among tobacco users. More than one-fourth of the study population used tobacco. The age-adjusted mortality rates were higher among tobacco users. The major causes of death among both users and non-users of tobacco were similar. The incidence proportion of death among all causes of death was higher for tobacco users. The hazard of mortality was significantly more among tobacco users, with the age-adjusted hazard ratio being 1.225 (1.140-1.315). The mortality risk due to tobacco use is high irrespective of the cause of death.


Coding Schemes in the Archerfish Optic Tectum.
Many studies have yielded valuable knowledge on the early visual system but it is biased since the studies have focused on terrestrial mammals alone. Here, to better account for visual systems in different environments and animal classes, we studied the structure of early visual processing in the archerfish which harnesses its extreme visual ability to hunt by shooting water jets at prey hanging on vegetation above the water. Thus, the archerfish provides a unique opportunity to study visual processing in a vertebrate which is an expert vision-guided predator with a very different brain structure than mammals. The receptive field structures in the archerfish (both sexes) optic tectum, the main visual processing region in the fish brain, were measured and linear non-linear cascades were used to analyze their properties. The findings indicate that the spatial receptive field structures lie on a continuum between circular and elliptical shapes. In addition, the cells' functional properties display a richness of response characteristics, since many cells could be captured by more than a single linear filter. Finally, the non-linear response functions that link linear filters and neuronal responses were found to be similar to the non-linear functions of models that describe terrestrial mammalian single cell activity. Overall our results help to better understand the early visual processing system across vertebrates.


Therapeutic misconceptions: when the voices of caring and research are misconstrued as the voice of curing.
Research on doctor-patient communication has characterized such interactions as being asymmetrical. The present article tries to shift emphasis away from the different orientations individuals bring to the communicative setting and attempts to highlight the different orientations ("voices") within a given individual. We draw on an in-depth analysis of discourse between a 21-year-old man who can be ascribed the roles of both patient and potential research subject and an interviewer who acts in both the role of medical staff and researcher. Focusing our analysis on a limited number of linguistic forms (pronouns and demonstratives), it is argued that the use of the same form for different referents signals a conflation of two voices -- the voice of health care ("caring") and the voice of "research." Furthermore, we argue that the voice of research is most likely to be interpreted by the patient/research subject within the framework of curing. As such, the present article promotes a shift in emphasis from different institutional -- and as such often assumed to be preexisting -- orientations between the communicating parties to differing orientations within the individual that cannot help but be misconstrued in terms of the curing voice. Our conclusion focuses on the ethical and discourse analytic implications of analyzing voices in a discussion.


The biomechanics of javelin throwing: a review.
In this paper, the scientific literature and that on the sports sciences relevant to javelin throwing is critically reviewed. This is particularly timely because of the change in the specification of the javelin for the men's event, which was introduced by the IAAF in 1986. A full discussion of the aerodynamics of the javelin is presented with due consideration of the change in pitching moment characteristics that the rules change had brought about. The uses and limitations of current computer programs for simulating javelin flight, in order to estimate optimal release parameters, are profiled. Consideration is also given to the effects of wind velocity, air density, javelin weight and the flutter and spin of the javelin on its flight. The review further considers the optimization of release parameters, drawing upon computer simulations and field-based data. The effects of release speed, release height, release angle, release angle of attack and release pitch rate are assessed. The javelin throwing technique is discussed in relation to cinematographically derived data, including an evaluation of experimental procedures. The importance to successful performance of the grip, the run-up and transition phases, the cross over and delivery strides are each reviewed. Finally, some prognoses as to the direction of future research into this complex throwing skill are offered.


Screening for strains with 11α-hydroxylase activity for 17α-hydroxy progesterone biotransformation.
Various corticosteroids are prepared by using 11α,17α-diOH-progesterone (11α,17α-diOH-PROG) as an important intermediate and raw material. Hence, strains that can improve the yields of 11α,17α-diOH-PROG should be screened. Cunninghamella elegans CICC40250 was singled out from five common 11α hydroxylation strains. The reaction parameters of 11α,17α-diOH-PROG production were also investigated. C. elegans CICC40250 could efficiently catalyze the hydroxylation of 17α-hydroxy progesterone (17α-OH-PROG) at C-11α position. This strain could also effectively convert 11α,17α-diOH-PROG at high substrate concentrations (up to 30g/L). After the coenzyme precursor glucose was added, the rate of 11α,17α-diOH-PROG formation reached 84.2%, which was 11.4% higher than that of the control group. Our study established a simple and feasible mechanism to increase 11α,17α-diOH-PROG production levels. This mechanism involves C. elegans CICC40250 that can be efficiently applied to induce the biotransformation of 17α-OH-PROG with a hydroxylation biocatalytic ability.


[A CASE OF PELVIC FRACTURE URETHRAL INJURY RECONSTRUCTED BY DEFERRED URETHROPLASTY].
We report a case of pelvic fracture urethral injury reconstructed by anastomotic urethroplasty. A 24-year-old male was referred to our hospital because of pelvic trauma accompanying ischial fracture. Retrograde urethrography showed urethral disruption and suprapubic catheter was inserted. One week later, we underwent endoscopic realignment. Three months later, we removed the Foley balloon catheter after we had checked that there was no stricture by the voiding cystourethrogram. However, 5 days after that, he came to our hospital because of urinary retention. Cystoscopy detected urinary stricture between bulbar and membranous urethra. We decided to do deferred urethroplasty. Five months after that we performed anastomotic urethroplasty. He was discharged 31 days after the operation. No stricture has been detected for 7 months postoperatively.


PART1 and hsa-miR-429-Mediated SHCBP1 Expression Is an Independent Predictor of Poor Prognosis in Glioma Patients.
Gliomas are the most common primary brain tumors. Because of their high degree of malignancy, patient survival rates are unsatisfactory. Therefore, exploring glioma biomarkers will play a key role in early diagnosis, guiding treatment, and monitoring the prognosis of gliomas. We found two lncRNAs, six miRNAs, and nine mRNAs that were differentially expressed by analyzing genomic data of glioma patients. The diagnostic value of mRNA expression levels in gliomas was determined by receiver operating characteristic (ROC) curve analysis. Among the nine mRNAs, the area under the ROC curve values of only CEP55 and SHCBP1 were >0.7, specifically 0.834 and 0.816, respectively. Additionally, CEP55 and SHCBP1 were highly expressed in glioma specimens and showed increased expression according to the glioma grade, and outcomes of high expression patients were poor. CEP55 was enriched in the cell cycle, DNA replication, mismatch repair, and P53 signaling pathway. SHCBP1 was enriched in the cell cycle, DNA replication, ECM receptor interaction, and P53 signaling pathway. Age, grade, IDH status, chromosome 19/20 cogain, and SHCBP1 were independent factors for prognosis. Our findings suggest the PART1-hsa-miR-429-SHCBP1 regulatory network plays an important role in gliomas.


How Lanthanide Ions Affect the Addition-Elimination Step of Methanol Dehydrogenases.
The recently discovered methanol dehydrogenase, XoxF, is a widespread enzyme used by methylotrophic bacteria to oxidize methanol for carbon and energy, and requires lanthanide ions for its activity. This enzyme represents an essential component of methanol utilization by both methanol- and methane-utilizing bacteria. The present investigation looks on the electronic, energetic and geometrical behavior of the methanol dehydrogenase from Methylacidiphilum fumariolicum SolV, which is strictly dependent on early lanthanide metals with +3 oxidation states, by examining enzyme-substrate complexes of all the lanthanides. We focus on the catalytic reaction mechanism of two methanol dehydrogenases having as cofactor europium and ytterbium belonging to the mid- and later- series of lanthanides, in comparison with the methanol dehydrogenase containing the cerium, one early lanthanide. Our results provide evidence for the influence of the lanthanide contraction effect in all the elementary steps of the catalytic reaction mechanism. This indication may prove useful for developing new catalytic machineries of enzymes that adopt new-to-nature transformations.


Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes.
Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.


Enhanced carotid body chemosensory activity and the cardiovascular alterations induced by intermittent hypoxia.
The carotid body (CB) plays a main role in the maintenance of the oxygen homeostasis. The hypoxic stimulation of the CB increases the chemosensory discharge, which in turn elicits reflex sympathetic, cardiovascular, and ventilatory adjustments. An exacerbate carotid chemosensory activity has been associated with human sympathetic-mediated diseases such as hypertension, insulin resistance, heart failure, and obstructive sleep apnea (OSA). Indeed, the CB chemosensory discharge becomes tonically hypereactive in experimental models of OSA and heart failure. Chronic intermittent hypoxia (CIH), a main feature of OSA, enhances CB chemosensory baseline discharges in normoxia and in response to hypoxia, inducing sympathetic overactivity and hypertension. Oxidative stress, increased levels of ET-1, Angiotensin II and pro-inflammatory cytokines, along with a reduced production of NO in the CB, have been associated with the enhanced carotid chemosensory activity. In this review, we will discuss new evidence supporting a main role for the CB chemoreceptor in the autonomic and cardiorespiratory alterations induced by intermittent hypoxia, as well as the molecular mechanisms involved in the CB chemosensory potentiation.


Metabolites and Changes in Antioxidant Activity of A-Type and B-Type Proanthocyanidin Dimers after Incubation with Rat Intestinal Microbiota.
Metabolism of B-type EC dimer, A-type EC dimer, A-type ECG dimer, and A-type EGCG dimer was compared in vitro after incubation with rat intestinal microbiota for 0-24 h. A "dimeric" catabolite (m/z 815.6) was detected in four procyanthocyanidin dimers. Although the early cleavage of the C4-C8 interflavan bond and the reductive cleavage of the C-ring occurred in both B-type and A-type dimers, the degradation routes of these two types of dimers might somewhat differ. A dimeric catabolite C1 and more low molecular weight phenolic acids were detected in the metabolites of A-type EC dimer, but not in B-type EC dimer. The antioxidant capabilities of the A-type dimers were enhanced significantly after incubation for 6 h, whereas the antioxidant capacity of B-type EC dimer decreased. The results suggested that changes in antioxidant activity of procyanidin dimers after bioconversion by rat intestinal microbiota were not only structure dependent but also incubation condition dependent.


Dose dependence and durability of the therapeutic effects of Asparagus cochinchinensis fermented extract in an ovalbumin-challenged asthma model.
The butanol extract of Asparagus cochinchinensis roots fermented with Weissella cibaria (BAfW) significantly suppressed the inflammatory response induced by lipopolysaccharide (LPS) treatment in RAW264.7 cells. To investigate the dose dependence and durability of BAfW on the anti-asthma effects, alterations in key parameters were measured in ovalbumin (OVA)-challenged Balb/c mice treated with the different doses of BAfW at three different time points. The number of immune cells, OVA-specific IgE level, thickness of respiratory epithelium and mucus score decreased significantly in a dose-dependent manner in response to treatment with 125 to 500 mg/kg BAfW (P<0.05), although the highest level was detected in the 500 mg/kg treated group. Moreover, the decrease in these parameters was maintained from 24 to 48 h in the 500 mg/kg of BAfW treated group. At 72 h, the effects of BAfW on the number of immune cells, OVA-specific IgE level and thickness of respiratory epithelium partially disappeared. Overall, this study provides the first evidence that the anti-asthma effect of BAfW may reach the maximum level in OVA-challenged Balb/c mice treated with 500 mg/kg and that these effects can last for 48 h.


Gabapentin's acute effect on mood profile -- a controlled study on patients with alcohol withdrawal.
Delayed beneficial effects of gabapentin on mood were frequently reported in various patient populations. This is the first controlled study which addressed acute effects of gabapentin on mood. Analysis of the German version of Profile of Mood States (POMS) throughout a randomised placebo-controlled, double-blinded study of gabapentin on acute alcohol withdrawal [Bonnet, U., Banger, M., Leweke, F.M., Specka, M., Müller, B.W., Hashemi, T., Nyhuis, P.W., Kutscher, S., Burtscheidt, W., Gastpar, M. 2003. Treatment of acute alcohol withdrawal with gabapentin -- results from a controlled two-center trial. J Clin Psychopharmacol 23, 514-519]. In addition, subjective severity of alcohol withdrawal was determined by the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) to control effects of concurrent withdrawal on POMS. Ratings were performed at intake (baseline), day 1 (study medication 400 mg q.i.d.), day 2 (study medication 400 mg q.i.d.) and day 7 (no study medication). Analyses could be performed on 46 out of 59 randomised subjects. Within the first two days of the study, a significant stronger increase in the POMS-vigour subscore occurred in the gabapentin group. A subgroup analysis suggests that gabapentin's effect on vigour largely results from a stronger improvement of vigour in a small group of 11 patients with co-morbid mild depression (according to ICD-10: dysthymia or depressive adjustment disorder). There were no significant differences between the treatment groups regarding the other POMS-subscores (dejection, fatigue, anger) ruling out an overall fast effect on mood. Moreover, ESA-measures were not significantly altered indicating a missing effect of 400 mg gabapentin q.i.d. on acute alcohol withdrawal itself. After tapering off study medication, no more significant differences between gabapentin and placebo group were observed on vigour, strongly suggesting that the initial effect results from a pharmacological gabapentin action. Gabapentin selectively accelerated the improvement of the vigour-subscore of patients with acute alcohol withdrawal within 48 h. This effect was independent from the subjective severity of withdrawal and especially marked in patients with co-morbid mild depression.


Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional protein.
In this report, we reinvestigate the only patient ever reported with a deficiency of peroxisomal 3-ketoacyl-CoA thiolase (THIO). At the time when they were described, the abnormalities in this patient, which included accumulation of very-long-chain fatty acids and the bile-acid intermediate trihydroxycholestanoic acid, were believed to be the logical consequence of a deficiency of the peroxisomal beta-oxidation enzyme THIO. In light of the current knowledge of the peroxisomal beta-oxidation system, however, the reported biochemical aberrations can no longer be explained by a deficiency of this thiolase. In this study, we show that the true defect in this patient is at the level of d-bifunctional protein (DBP). Immunoblot analysis revealed the absence of DBP in postmortem brain of the patient, whereas THIO was normally present. In addition, we found that the patient had a homozygous deletion of part of exon 3 and intron 3 of the DBP gene, resulting in skipping of exon 3 at the cDNA level. Our findings imply that the group of single-peroxisomal beta-oxidation-enzyme deficiencies is limited to straight-chain acyl-CoA oxidase, DBP, and alpha-methylacyl-CoA racemase deficiency and that there is no longer evidence for the existence of THIO deficiency as a distinct clinical entity.


Two fiber-bundle-type FI/FO devices of low insertion loss and cross talk applied for connecting 13-core 5-mode fiber.
Two fiber-bundle-typed fan-in/fan-out (FI/FO) devices, "wavy hexagon-shaped silhouette" type (W-FI/FO) and "tortoise-shaped silhouette" type (T-FI/FO), have been proposed and manufactured based on tapering glass tubes for docking with a self-made 13-core 5-mode fiber. The W-FI/FO device consists of 19 5-mode fibers and has an extended layout based on the 13-core 5-mode fiber structure. It could dock multiple fibers with 19 or 13 cores of the same size standards. When connecting it with 13-core 5-mode, the average losses (ILs) of its five modes are 1.07 dB, 2.95 dB, 3.42 dB, 3.65 dB, and 4.38 dB. The cross talks of the five linearly polarized (LP) modes are -69.1 dB, -64.7 dB, -44.2 dB, -43.9 dB, and -39.1 dB. The T-FI/FO device has a similar core arrangement to the 13-core 5-mode fiber and its average ILs of the five LP modes are 0.23 dB, 1.31 dB, 2.09 dB, 2.66 dB, and 3.03 dB. The cross talks of its five LP modes between adjacent cores are -72.8 dB, -67.8 dB, -43.6 dB, -40.0 dB, and -35.3 dB. The IL and cross talk of the LP01 mode are of satisfactory values, which are 0.23 dB and -72.8 dB, respectively. These two proposed FI/FO devices are expected to be used for high-speed optical interconnection and fiber communication.


Magneto-Chiral Dichroism in a One-Dimensional Assembly of Helical Dysprosium(III) Single-Molecule Magnets.
Here we report magneto-chiral dichroism (MChD) detected through visible and near-infrared light absorption of a chiral dysprosium(III) coordination polymer. The two enantiomers of [DyIII(H6(py)2)(hfac)3]n [H6(py)2 = 2,15-bis(4-pyridyl)ethynylcarbo[6]helicene; hfac- = 1,1,1,5,5,5-hexafluoroacetylacetonate], where the chirality is provided by a functionalized helicene ligand, were structurally, spectroscopically, and magnetically investigated. Magnetic measurements reveal a slow relaxation of the magnetization, with differences between enantiopure and racemic systems rationalized on the basis of theoretical calculations. When the enantiopure complexes are irradiated with unpolarized light in a magnetic field, they exhibit multiple MChD signals associated with the f-f electronic transitions of DyIII, thus providing the coexistence of MChD-active absorptions and single-molecule-magnet (SMM) behavior. These findings clearly show the potential that rationally designed chiral SMMs have in enabling the optical readout of magnetic memory through MChD.


Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice.
The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR. The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks. While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.


[Metabolic bone and joint diseases].
Metabolic bone and joint diseases in adults include osteomalacia, rheumatoid arthritis, gouty arthritis. Recently, the newest molecular biology procedures and the clinical observation studies can produce good results for understanding of these diseases. From this perspective, the author introduced updated information of the pathophysiology, the latest diagnostic criteria and the therapy of these diseases.


A double-blind, side-by-side comparison study of low fluence long pulse dye laser to coolant treatment for wrinkling of the cheeks.
Nonablative laser resurfacing with various lasers and light sources can improve skin texture and fine lines. The 595 nm pulsed dye laser has been reported to improve rhytides through nonablative mechanisms, minimizing the side effects and recovery period associated with traditional ablative resurfacing techniques. The purpose of this study was to investigate the efficacy of the long pulse flashlamp pumped pulsed dye laser (LPDL) in improving rhytides and stimulating collagen synthesis and dermal remodeling. The cheeks of 15 women with moderate to severe photoaging were treated on one side with a series of four monthly LPDL treatments, while the contralateral cheek was treated with cryogen coolant only. Clinical grading was performed at monthly intervals for up to 3 months after the fourth LPDL treatment. Skin biopsy before treatment and at 4-6 weeks was also performed for histologic evaluation and staining for type I procollagen. Eleven of 15 patients demonstrated improvement of the laser-treated cheek while only three of 15 patients the demonstrated improvement on the cryogen-treated cheek. A statistically significant (p = 0.0035) improvement in clinical grading of photodamage was noted in the treated side versus the control. In those patients who improved with LPDL treatment, an improvement of 18.1% in the mean pre- and post-treatment clinical grading scores was observed. Histologic evaluation demonstrated an increase in activated fibroblasts with positive procollagen staining on the LPDL-treated cheek. The 595 nm LPDL may be used in the treatment of moderate to severe wrinkles. A mild improvement may be expected with minimal to no side effects.


Medicinal Plants and Natural Products Used in Cataract Management.
Cataract is the leading reason of blindness worldwide and is defined by the presence of any lens opacities or loss of transparency. The most common symptoms of cataract are impaired vision, decreased contrast sensitivity, color disturbance, and glare. Oxidative stress is among the main mechanisms involved in the development of age-related cataract. Surgery through phacoemulsification and intraocular lens implantation is the most effective method for cataract treatment, however, there are chances of serious complications and irreversible loss of vision associated with the surgery. Natural compounds consisting of antioxidant or anti-inflammatory secondary metabolites can serve as potential leads for anticataract agents. In this review, we tried to document medicinal plants and plant-based natural products used for cataract treatment worldwide, which are gathered from available ethnopharmacological/ethnobotanical data. We have extensively explored a number of recognized databases like Scifinder, PubMed, Science Direct, Google Scholar, and Scopus by using keywords and phrases such as "cataract", "blindness", "traditional medicine", "ethnopharmacology", "ethnobotany", "herbs", "medicinal plants", or other relevant terms, and summarized the plants/phytoconstituents that are evaluated in different models of cataract and also tabulated 44 plants that are traditionally used in cataract in various folklore medical practices. Moreover, we also categorized the plants according to scientific studies carried out in different cataract models with their mechanisms of action.


Enhanced and Facet-specific Electrocatalytic Properties of Ag/Bi2Fe4O9 Composite Nanoparticles.
Ag/Bi2Fe4O9 nanoparticles (BFO NPs) have been synthesized using a two-step approach involving glycine combustion and visible light irradiation. Their structures were characterized in detail using X-ray diffraction, transmission electron microscope, scanning electron microscopy, and scanning transmission electron microscopy techniques. Their electrocatalytic properties were studied through enzymatic glucose detection with an amperometric biosensor. The Ag deposited on selective crystal facets of BFO NPs significantly enhanced their electrocatalytic activity. To gain insights into the origin of the enhanced electrocatalytic activities, we have carried out studies of Ag+ reduction and Mn2+ oxidation reaction at the {200} and {001} facets, respectively. The results suggest effective charge separation on the BFO NP surfaces, which is likely responsible for the enhanced electrocatalytic properties. Furthermore, enhanced ferromagnetism was observed after the Ag deposition on BFO NPs, which may be related to the improved electrocatalytic properties through spin-dependent charge transport. The facet-specific electrocatalytic properties are highly interesting and desired for chemical reactions. This study demonstrates that Ag/BFO NPs are potentially useful for electrocatalytic applications including biosensing and chemical synthesis with high product selectivity.


Tracking of proinflammatory collagen-specific T cells in early and late collagen-induced arthritis in humanized mice.
Rheumatoid arthritis is a chronic inflammatory disease associated with certain HLA-DR4 subtypes. The target autoantigen(s) is unknown, but type II collagen (CII) is a candidate, with a single immunodominant DR4-restricted 261-273 T cell epitope (CII(261-273)). In the present study, we have prepared HLA-DR4:CII(261-273) tetramers and analyzed peripheral blood, lymph node, and synovial fluid cells from DR4-transgenic mice with early and late collagen-induced arthritis to draw a fuller picture of the role of CII-reactive Th cells in disease development. Their frequencies increased approximately 20-fold in blood 1-2 wk postimmunization, and even more in acutely arthritic joints. Our data strongly suggest that CII-specific Th cells are necessary, but not sufficient for collagen-induced arthritis. The CII-specific Th cells displayed an activated proinflammatory Th1 phenotype, and their expansion correlated with onset and severity of arthritis and also with anti-CII Ab levels. Surprisingly, shortly after the first clinical signs of arthritis, activated HLA-DR4:CII tetramer(+) cells became undetectable in the synovial fluid and rare in the blood, but persisted in lymph nodes. Consequently, future human studies should focus on patients with early arthritis, and on their synovial cells, to re-evaluate the occurrence and pathogenic importance of CII-specific or other Th cells in rheumatoid arthritis.


Long-term quality of life and psycho-social outcomes after oropharyngeal cancer surgery and radial forearm free-flap reconstruction: A GETTEC prospective multicentric study.
To assess long-term quality of life (QoL) and psycho-social outcomes, and to determine their predictive factors after oropharyngeal cancer (OPC) surgery and radial forearm free-flap (RFFF) reconstruction. Patients who had undergone OPC surgery and RFFF reconstruction who were still alive and disease-free at least 1 year after surgery were enrolled in this prospective multicentric study. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core (QLQ-C30) and Head and Neck Cancer (QLQ-H&N35) QoL questionnaires, the Voice Handicap Index (VHI-10) questionnaire and the Hospital Anxiety and Depression Scale (HADS). The level of dysphagia was evaluated using the Dysphagia Handicap Index (DHI) and the Dysphagia Outcomes and Severity Scale (DOSS). Predictive factors of these clinical outcomes were determined in univariate and multivariate analysis. A total of 58 patients were included in this study. Long-term QoL and functioning scales scores were well-preserved (all superior to 70%). Main persistent symptoms were fatigue, reduced sexuality and oral function-related disorders (swallowing, teeth, salivary and mouth-opening problems). HADS anxiety and depression scores were 7.2 and 5.4, respectively. Twenty-one (36%) patients presented an anxiodepressive disorder (HADS global score ≥ 15). Among the 21 patients who were still working before surgery, 11 (52%) had returned to work at the time of our study. The HADS global score (p < 0.001) was the main predictor of QoL, VHI-10 and DOSS scores. Psychological distress is the main determinant of long-term QoL and is therefore of critical importance in the multidisciplinary management of OPC patients.


The potential impact of post-COVID symptoms in the healthcare sector.
The phenomenon of post-COVID syndrome (PCS) is evolving from an abstract array of non-specific symptoms to an identifiable clinical entity of variable severity. Its frequency and persistence have implications for service delivery and workforce planning. This study was aimed to assess the prevalence of symptoms consistent with PCS and the subjective degree of recovery in a cohort of healthcare workers, focusing on those who have returned to work. A study population of 1176 was surveyed when attending for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody testing. Two sub-groups were identified: those with known (i.e. diagnosed on PCR testing) and assumed (i.e. antibody evidence of previous infection) SARs-CoV-2 infection, at least 12 weeks prior to the study. Each group was asked about their subjective degree of recovery and the nature of their persistent symptoms. Results were analysed via excel and SPSS. In total, 144 employees showed PCR evidence of previous infection, with 139 of these being infected at least 12 weeks prior to the study. Of these 139, only 19% (n = 26) reported feeling 100% recovered, and 71% reported persistent symptoms. Of those with assumed SARS-CoV-2 infection (n = 78), 32 (41%) were truly asymptomatic since the commencement of the pandemic, while 46 (59%) described symptoms suggestive of possible infection at least 12 weeks prior to the study. Of this latter group, 23% (n = 18) also reported residual symptoms. PCS is prevalent among this group, including those not previously diagnosed with COVID-19. Its' frequency and duration present challenges to employers with regards to the management of work availability and performance.


Nutrient Removal by Grain in Modern Soybean Varieties.
Knowing the nutrient removal by soybean grain harvest in different varieties, locations, and over time is essential to correctly adjust agronomic recommendations, update farmers' practices, and increase nutrient use efficiency. A field-based research trial was carried out to assess macronutrients [nitrogen (N), phosphorus (P), potassium (K), magnesium (Mg), calcium (Ca), and sulfur (S)] removed in grain by modern soybean varieties from southern Brazil introduced between 2007 and 2016. We examined changes between our set of modern varieties and a dataset of historical values encompassing a wide range of varieties introduced before 2007. Moreover, we undertook a synthesis analysis using scientific literature published after 2007 to investigate nutrient removal by grain among modern Brazilian soybeans and a dataset that included field trials from Argentina, United States, and India. There were no yield gains across the years for modern soybean varieties introduced among 2007 and 2016 in Brazil, although the grain N and Mg concentrations decreased. Modern Brazilian soybeans increased nutrient removal compared with that by soybeans historically planted in Brazil, with 11.1, 26.9, 45.0, and 31.6% more N, P, K, and Mg removed, respectively. Our results indicated that soybean growing in Brazil removed 4.3% less N relative to the values reported in the literature dataset, whereas K removal was 21.4% greater. A significant difference was also recorded for high-yield soybean varieties, and Brazilian varieties removed 11.8% less N and 8.6% more K than varieties in the literature dataset. No differences were found among locations for P removal, averaging 4.9 kg Mg-1 grain. In conclusion, this study indicates that the amounts of nutrients removed by modern soybean varieties were greater relative to the historical values recorded in Brazil, excluding Ca and S. Nonetheless, in the middle to long term (10 years), a significant impact of plant breeding on grain nutrient concentration was recorded only for N and Mg. The difference in nutrient removal patterns between Brazil and other countries indicates an integrated effect of management, genotype, and environment on nutrient removal. These findings provide guidance for optimal nutrient management and specific information for plant breeding programs to understand nutrient variability.


[Combined use of bare stent and coils in the treatment of aortic dissection with distal tear at celiac trunk].
To evaluate a novel method of combining use of bare stent and coils in the treatment of aortic dissection with distal tear at celiac trunk. From April 2007 to August 2010, two cases of Stanford type B dissections underwent initially endovascular stent-grafting to seal proximal tears while distal tears at celiac trunks failed to seal spontaneously. Bare stents were then implanted into celiac trunks crossing tears. And an appropriate amount of coils were pushed into false lumen via a catheter passing through the holes of stents for maintaining the patency of celiac trunk and sealing tears. Both procedures succeeded. False lumen was indistinct on angiography while celiac trunks were patent. No complication occurred. After the follow-up periods of 5 and 2 years respectively, false lumen disappeared and celiac arteries became patent. The novel method of combining use of bare stent and coils is technically simple. It required a simple puncture. Major traumas of open and hybrid operations are avoided. It is also indicated for cases of tears at renal or superior mesenteric arteries. As a supplemental method for conventional TEVAR, radical cure may be achieved for some complicated Stanford B dissections.


Effect of radiotherapy on brain glucose metabolism in patients operated on for low grade astrocytoma.
To assess the effect of postoperative radiotherapy on brain glucose metabolism (CMRGlu) of operated patients with low grade astrocytomas. PET and 18F-fluorodeoxyglucose was used to measure absolute CMRGlu in patients with fibrillary astrocytoma (WHO II) of the frontal lobe, who did (n=7) or did not (n=12) receive radiotherapy subsequent to first debulking tumour resection. In addition, statistical parametric mapping (SPM95) was applied to assess the pattern of relative CMRGlu associated with the frontal tumour. Data were compared with 12 healthy controls. A global reduction of absolute CMRGlu was found when either patients with or without radiotherapy were compared with controls (ROI analysis). Brain areas of relative CMRGlu reduction were found in the brain ipsilateral and contralateral to the tumour, comparing both patient groups with controls by SPM ("tumour diaschisis effect"). Superimposed, absolute CMRGlu in the contralateral frontal, parietal, occipital cortex as well as in the white matter was on average 17% lower in patients receiving radiotherapy than in patients who did not. The data discriminate a tumour effect from a radiotherapy effect, and support the view of adverse effects of radiotherapy on brain not directly involved by tumour.


A Novel CRISPR Interference Effector Enabling Functional Gene Characterization with Synthetic Guide RNAs.
While CRISPR interference (CRISPRi) systems have been widely implemented in pooled lentiviral screening, there has been limited use with synthetic guide RNAs for the complex phenotypic readouts enabled by experiments in arrayed format. Here we describe a novel deactivated Cas9 fusion protein, dCas9-SALL1-SDS3, which produces greater target gene repression than first or second generation CRISPRi systems when used with chemically modified synthetic single guide RNAs (sgRNAs), while exhibiting high target specificity. We show that dCas9-SALL1-SDS3 interacts with key members of the histone deacetylase and Swi-independent three complexes, which are the endogenous functional effectors of SALL1 and SDS3. Synthetic sgRNAs can also be used with in vitro-transcribed dCas9-SALL1-SDS3 mRNA for short-term delivery into primary cells, including human induced pluripotent stem cells and primary T cells. Finally, we used dCas9-SALL1-SDS3 for functional gene characterization of DNA damage host factors, orthogonally to small interfering RNA, demonstrating the ability of the system to be used in arrayed-format screening.


A diagnostic model incorporating P50 sensory gating and neuropsychological tests for schizophrenia.
Endophenotypes in schizophrenia research is a contemporary approach to studying this heterogeneous mental illness, and several candidate neurophysiological markers (e.g. P50 sensory gating) and neuropsychological tests (e.g. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST)) have been proposed. However, the clinical utility of a single marker appears to be limited. In the present study, we aimed to construct a diagnostic model incorporating P50 sensory gating with other neuropsychological tests in order to improve the clinical utility. We recruited clinically stable outpatients meeting DSM-IV criteria of schizophrenia and age- and gender-matched healthy controls. Participants underwent P50 sensory gating experimental sessions and batteries of neuropsychological tests, including CPT, WCST and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). A total of 106 schizophrenia patients and 74 healthy controls were enrolled. Compared with healthy controls, the patient group had significantly a larger S2 amplitude, and thus poorer P50 gating ratio (gating ratio = S2/S1). In addition, schizophrenia patients had a poorer performance on neuropsychological tests. We then developed a diagnostic model by using multivariable logistic regression analysis to differentiate patients from healthy controls. The final model included the following covariates: abnormal P50 gating (defined as P50 gating ratio >0.4), three subscales derived from the WAIS-III (Arithmetic, Block Design, and Performance IQ), sensitivity index from CPT and smoking status. This model had an adequate accuracy (concordant percentage = 90.4%; c-statistic = 0.904; Hosmer-Lemeshow Goodness-of-Fit Test, p = 0.64>0.05). To the best of our knowledge, this is the largest study to date using P50 sensory gating in subjects of Chinese ethnicity and the first to use P50 sensory gating along with other neuropsychological tests to develop a diagnostic model for schizophrenia. Further research to validate the predictive accuracy of this model by applying it on other samples is warranted.


Pharmacological investigations of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M 73101), a new analgesic and anti-inflammatory drug.
Analgesic, anti-inflammatory and other related actions of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101) were investigated in experimental animals, and the following results were obtained: Analgesic activity of M73101 was more potent than that of other anti-inflammatory drugs except for aminopyrine in phenylquinone test in mice. M73101 showed the most potent analgesic activity among the drugs tested in Randall-Selitto test in rats. The mode of analgesic action of M73101 resembled that of aminopyrine. M73101 possessed potent inhibitory activities on acute inflammatory edema and suppressed the permeability of capillary vessels. M73101 inhibited histamine release from isolated rat mast cells (in vitro) and rat skin (in vivo) by the condensation product of N-methyl-homoanisylamine formaldehyde (compound 48/80), and leucocyte emigration in carrageenin rat pleurisy. M73101 was much less active than phenylbutazone and other anti-inflammatory drugs in causing gastric lesion. Considering from therapeutic index, M73101 was found to be much superior to mepirizole, tiaramide, benzydamine, phenylbutazone and acetylsalicylic acid.


Mediators of Atherosclerosis in South Asians Living in America: Use of Web-Based Methods for Follow-Up and Collection of Patient-Reported Outcome Measures.
A key challenge for longitudinal cohort studies is follow-up and retention of study participants. Participant follow-up in longitudinal cohort studies is costly and time-consuming for research staff and participants. This study determined the feasibility and costs of using Web-based technologies for follow-up and collection of patient-reported outcomes in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study. The MASALA study is a community-based cohort of 906 South Asians in the United States. Since the baseline in-person visits (2010-2013), a yearly telephone follow-up survey was used to assess participants' health status and incidence of cardiovascular disease. A Web-based version of the follow-up survey was developed using the REDCap (Research Electronic Data Capture) Web app. Participants from the Chicago field center who were due for their annual follow-up and who had a valid email address were sent an email link to a secure online portal where they could complete the survey. Telephone follow-up was used with nonresponders. A link to the Web survey was emailed to 285 participants (February to October 2014) and the overall completion rate was 47.7% (136/285). One-third of participants who were unresponsive (n=36) to annual telephone follow-up completed the Web survey. Web responders were younger, more likely to be married, and to have higher education and income compared (P<.05) to telephone-only responders. Web survey development involved 240 hours of research staff time. Since launching, the Web-based survey has required 3 hours per week of staff time. Although electronic follow-up will not be a panacea for cohort operations, it will serve as an adjunctive strategy to telephonic follow-up for maximizing cohort retention with lower costs.


The ABCs of finding a good antibody: How to find a good antibody, validate it, and publish meaningful data.
Finding an antibody that works for a specific application can be a difficult task. Hundreds of vendors offer millions of antibodies, but the quality of these products and available validation information varies greatly. In addition, several studies have called into question the reliability of published data as the primary metric for assessing antibody quality. We briefly discuss the antibody quality problem and provide best practice guidelines for selecting and validating an antibody, as well as for publishing data generated using antibodies.


Integrated management strategies for Amblyomma americanum (Acari: Ixodidae) on pastured beef cattle.
Data on tick control and knowledge of the damage caused to beef cattle by tick feeding were incorporated into a computerized dynamic life table model (LSTSIM) for Amblyomma americanum (L.). Simulations were made to determine economically feasible, 5-yr integrated pest management (IPM) strategies for A. americanum in forage areas utilized by Bos taurus, Bos indicus, and crossbred cattle (B. taurus x B. indicus). The effects of host resistance, pasture rotation, habitat conversion, topical acaricides, systemic acaricides, and the area-wide application of acaricides to pastures on populations of parasitic female ticks were simulated as individual control technologies and as components of multiple-factor IPM strategies. The most effective, single-factor control strategy for A. americanum in beef cattle forage areas is the use of tick-resistant B. indicus cattle. Pasture rotation combined with area-wide acaricide applications was the only economically feasible IPM strategy for B. indicus cattle and reduced tick densities by 89% after 5 yr. Thirteen economically feasible IPM strategies were identified for use with B. taurus cattle. Of these, the most efficacious was pasture rotation in May combined with systemic or topical acaricide applications. Other strategies included systemic acaricides with area-wide acaricide applications to pastures, topical acaricides with area-wide acaricide applications, pasture rotation with habitat conversion and topical acaricides, and pasture rotation with habitat conversion, topical acaricides, and area-wide acaricide applications. Each technology reduced tick densities on B. taurus cattle by > 80% over a 5-yr period. Nine IPM strategies were economically feasible for use with crossbred cattle. Of these, pasture rotation combined with systemic or topical acaricide applications reduced the number of female ticks on cattle by > 84%; pasture rotation combined with habitat conversion reduced tick numbers by 77%. The most effective nonacaricide-based IPM strategy for B. taurus and crossbred cattle was pasture rotation combined with habitat conversion. No acaricide-free IPM strategy was economically feasible for use with B. indicus cattle.


Metabolic syndrome distribution based on diagnostic criteria and family history among adults in Al-Basra, Iraq.
Metabolic syndrome (MetS) is a collection of cardiovascular risk factors induced by insulin resistance and an inflammatory state that increases the likelihood of developing type 2 diabetes and a variety of cardiovascular disorders. The study aims to determine the distribution of MetS by diagnostic criteria and family history among adults in Al- Basra province, southern Iraq. A cross-sectional study was conducted at the Al- Fiaha Specialized Diabetes, Endocrine, and Metabolism Center (FDEMC) from October 2nd, 2022, to May 1st, 2023. Following ethical approval, data was obtained using a pre-tested questionnaire. All patient information was obtained from direct interviews as well as FDEMC's digital records, which controlled patient data via a Microsoft Access program and an internal network. This study included 476 people, aged 19 to 89. The sample had an equal number of males and females (238). MetS was identified in 247 people in the entire sample using the International Diabetes Federation criteria. The proportion of participants with a family history was as follows: obesity (30.0%), hypertension (44.1%), diabetes mellitus (46.6%), and cardiovascular disease (9.3%). The diagnostic criteria for MetS were as follows: high wc (94.3%), elevated glucose (69.6%), reduced highdensity lipoprotein (HDL) (80.2%), elevated TG (40.5%), and hypertension (71.7%). Controlled on glycemic status (21.1%), hypertension (61.9%), and lipids (44.1%). Large wc, reduced HDL, and family histories of obesity, hypertension, diabetes mellitus, or cardiovascular disease are the most important risk factors for MetS. Participants with MetS have difficulties controlling their blood sugar, but they regulate the other MetS components.


Mouse models of autoimmune blistering diseases induced by the passive transfer of antibodies.
Passive transfer of IgG into neonatal mice is a potential method of reproducing antibody-mediated blistering skin diseases. The major autoantigen for bullous pemphigoid is collagen XVII (COL17)/BP180, which is an epidermal linker transmembrane protein. A single intraperitoneal injection of human or rabbit IgG against pathogenic epitopes for COL17 can induce skin fragility in neonatal mice that express human COL17. Since amino acid sequences of the pathogenic epitopes for COL17 significantly differ between humans and rodents, the required antibodies are those that correctly target the molecule to induce the blistering phenotype.


Do subsidization and monitoring enhance adherence to prescribed exercise?
We studied whether partial versus full subsidization and self versus other monitoring promote adherence to physician-prescribed exercise. We randomly assigned 132 participants to experimental conditions defined by two levels of subsidization and two types of monitoring. Physicians wrote prescriptions as referrals to an exercise facility. A computer recorded participants' exercise for 12 weeks. A sponsoring medical organization paid half or all of the facility's fees. Half of the participants kept records of workouts, and half reported workouts to researchers who telephoned them. Fully subsidized patients averaged 21.41 workouts versus 16.67 workouts by partially subsidized patients (p < .05). Researcher-monitored participants averaged 22.14 workouts versus 15.96 workouts by self-monitored participants (p < .01). Full subsidization and third-party monitoring increased exercise rates. These findings encourage use of both to enhance prescribed exercise rates and continued study of factors that contribute to the efficacy of prescribed exercise.


Magnesium for Dynamic Nanoplasmonics.
The key component of nanoplasmonics is metals. For a long time, gold and silver have been the metals of choice for constructing plasmonic nanodevices because of their excellent optical properties. However, these metals possess a common characteristic, i.e., their optical responses are static. The past decade has been witnessed tremendous interest in dynamic control of the optical properties of plasmonic nanostructures. To enable dynamic functionality, several approaches have been proposed and implemented. For instance, plasmonic nanostructures can be fabricated on stretchable substrates or on programmable templates so that the interactions between the constituent metal nanoparticles and therefore the optical responses of the plasmonic systems can be dynamically changed. Also, plasmonic nanostructures can be embedded in tunable dielectric materials, taking advantage of the sensitive dependence of the localized surface plasmon resonances on the neighboring environment. Another approach, which is probably the most intriguing one, is to directly regulate the carrier densities and dielectric functions of the metals themselves. In this Account, we discuss a relatively new metal in nanoplasmonics, magnesium, and its important role in the development of dynamic plasmonic nanodevices at visible frequencies. We first elucidate the basic optical properties of Mg and compare it with conventional plasmonic materials such as Au, Ag, and others. Then we describe a unique characteristic of Mg, i.e., its reversible phase transitions between the metallic state and a dielectric state, magnesium hydride, through hydrogenation and dehydrogenation. This sets the basis for Mg in dynamic nanoplasmonics. In particular, the structural properties and dielectric functions of the two distinct states are discussed in detail. Subsequently, we highlight the experimental investigations of the physical mechanisms and nanoscale understanding of Mg nanoparticles during hydrogenation and dehydrogenation. We then introduce a plethora of newly developed Mg-based dynamic optical nanodevices for applications in plasmonic chirality switching, dynamic color displays with Mg nanoparticles and films, and dynamic metasurfaces for ultrathin and flat optical elements. We also outline strategies to enhance the stability, reversibility, and durability of Mg-based nanodevices. Finally, we end this Account by outlining the remaining challenges, possible solutions, and promising applications in the field of Mg-based dynamic nanoplasmonics. We envision that Mg-based dynamic nanoplasmonics will not only provide insights into understanding the catalytic processes of hydrogen diffusion in metals by optical means but also will open an avenue toward functional plasmonic nanodevices with tailored optical properties for real-world applications.


Intraoperative Fluorescent Image Guidance for Nerve-Sparing Prostatectomy: A Review of Historical Context and Current Research.
Fluorescent probes in the near-infrared (NIR) range have immense potential to improve observation of positive margins, lymph nodes, and nerves in prostatectomy. Development of fluorescent dyes and mechanisms of cellular uptake paved the way for the current emerging technologies. However, intracellular transport of fluorophores proved to be logistically challenging with respect to intraoperative deployment. Peptide-based probes with high specificity for nerves enabled broader and more rapid labeling. Key features of the ideal probe include selectivity, minimal background noise, safety, and low cost. Human neuropeptide 401 (HNP401) and oxazine-based probes perform well in these categories. As for tumor-specific labeling, prostate specific membrane antigen is relatively selective for the prostate and can be conjugated to a fluorophore. NIR spectrum emission is an ideal range for clinical imaging use, as fluorescence occurs outside the field of visible light, and tissue optical properties diverge significantly at the visible-NIR transition. Indocyanine, carbocyanine, and fluorescein derivatives are common fluorophore conjugates for the probes. Finally, to harness the power of fluorescence intraoperatively, the surgeon must look through a specialized lens. Multiphoton microscopy, optical coherence tomography, and confocal laser endomicroscopy have emerged as frontrunners in this arena. As with any evolving technology, ongoing research is expanding the applications of fluorescent intraoperative imaging in prostate surgery. Innovations in camera technology, dye selection, and image processing are refining the technique's capabilities. A core challenge of these technologies translating into the operating room relates to size and the ability to view objects at vastly different magnifications. Dual modality zoom settings are promising solutions. Furthermore, interdisciplinary collaboration between surgeons, imaging specialists, and researchers continues to drive advancements. In conclusion, fluorescent intraoperative imaging has the potential to usher in a new era of precision and safety in prostate surgery.


Saponins in pulses and their health promoting activities: A review.
Saponins are a class of natural compounds present in pulses having surface active properties. These compounds show variation in type, structure and composition of their aglycone moiety and oligosaccharide chains. Saponins have plasma cholesterol lowering effect in humans and are important in reducing the risk of many chronic diseases. Moreover, they have shown strong cytotoxic effects against cancer cell lines. However, more epidemiological and clinical studies are required for the proper validation of these health promoting activities. Processing and cooking promotes the loss of saponins from foods. The effect of soaking, sprouting and cooking on the stability and bioavailability of saponins in pulses is an important area which should be thoroughly worked out for achieving desirable health benefits. In the present review, the structures, contents and health benefits of saponins present in pulses are discussed. Moreover, the effect of processing (of pulses) on the saponins is also highlighted.


Visual results after microsurgical removal of meningiomas involving the anterior visual system.
Visual results were evaluated in 20 patients after microsurgical removal of intracranial meningiomas that had produced visual loss from damage to the anterior visual system. Patients were evaluated preoperatively, immediately postoperatively, and several months to years after surgery. Visual acuity either improved or remained normal in 68.75% (22/32) of eyes examined and worsened in 25% (8/32) of eyes examined. Visual field changes generally paralleled visual acuity changes. Visual results were most closely related to duration of visual symptoms and not to either tumor size or preoperative visual findings.


Trajectory of treatment response in the child and adolescent migraine prevention (CHAMP) study: A randomized clinical trial.
Identify preventive medication treatment response trajectories among youth participating in the Childhood and Adolescent Migraine Prevention study. Data were evaluated from 328 youth (ages 8-17). Childhood and Adolescent Migraine Prevention study participants completed headache diaries during a 28-day baseline period and a 168-day active treatment period during which youth took amitriptyline, topiramate, or placebo. Daily headache occurrence trajectories were established across baseline and active treatment periods using longitudinal hierarchical linear modeling. We tested potential treatment group differences. We also compared final models to trajectory findings from a clinical trial of cognitive behavioral therapy plus amitriptyline for youth with chronic migraine to test for reproducibility. Daily headache occurrence showed stability across baseline. Active treatment models revealed decreases in headache frequency that were most notable early in the trial period. Baseline and active treatment models did not differ by treatment group and replicated trajectory cognitive behavioral therapy plus amitriptyline trial findings. Replicating headache frequency trajectories across clinical trials provides strong evidence that youth can improve quickly. Given no effect for medication, we need to better understand what drives this clinically meaningful improvement. Results also suggest an expected trajectory of treatment response for use in designing and determining endpoints for future clinical trials.Trial Registration. ClinicalTrials.gov Identifier: NCT01581281.


Glycometabolic reprogramming in cementoblasts: A vital target for enhancing cell mineralization.
Cementum, a constituent part of periodontal tissues, has important adaptive and reparative functions. It serves to attach the tooth to alveolar bone and acts as a barrier delimit epithelial growth and bacteria evasion. A dynamic and highly responsive cementum is essential for maintaining occlusal relationships and the integrity of the root surface. It is a thin layer of mineralized tissue mainly produced by cementoblasts. Cementoblasts are osteoblast-like cells essential for the restoration of periodontal tissues. In recent years, glucose metabolism has been found to be critical in bone remodeling and osteoblast differentiation. However, the glucose metabolism of cementoblasts remains incompletely understood. First, immunohistochemistry staining and in vivo tracing with 18 F-fluorodeoxyglucose (18 F-FDG) revealed significantly higher glucose metabolism in cementum formation. To test the bioenergetic pathways of cementoblast differentiation, we compared the bioenergetic profiles of mineralized and unmineralized cementoblasts. As a result, we observed a significant increase in the consumption of glucose and production of lactate, coupled with the higher expression of glycolysis-related genes. However, the expression of oxidative phosphorylation-related genes was downregulated. The verified results were consistent with the RNA sequencing results. Likewise, targeted energy metabolomics shows that the levels of glycolytic metabolites were significantly higher in the mineralized cementoblasts. Seahorse assays identified an increase in glycolytic flux and reduced oxygen consumption during cementoblast mineralization. Apart from that, we also found that lactate dehydrogenase A (LDHA), a key glycolysis enzyme, positively regulates the mineralization of cementoblasts. In summary, cementoblasts mainly utilized glycolysis rather than oxidative phosphorylation during the mineralization process.


Lipase and antibacterial activities of a recombinant protein from the accessory glands of female Phlebotomus papatasi (Diptera: Psychodidae).
The reproductive accessory glands of the adult female have a functional versatility in insects, contributing to reproduction in various ways. The major protein secreted by the accessory glands of female Phlebotomus papatasi (Diptera, Psychodidae) has already been characterised and named PhpaLIP (for P. papatasi lipase) because, in terms of its amino-acid sequence, it is very similar to a wide range of vertebrate lipases. The gene coding for PhpaLIP has now been cloned into a pQE30 vector and expressed in Escherichia coli. When the recombinant PhpaLIP was tested in vitro, it was found to have not only lipase-like activity (when p-nitrophenyl caprylate was used as the substrate) but also specific antibacterial activity against some Gram-positive and Gram-negative bacteria. The possible physiological roles of PhpaLIP in P. papatasi are discussed, in the light of these results.


Student life - Twitter - a great medium for learning and debate.
Twitter is ideal for nurses and nursing students to start a discussion and debate, share innovative practice and, as lifelong learners, keep up to date with evidence-based care. The social media platform is often the first place new ideas and concepts are aired. Even if you don't tweet, it is likely you know about campaigns that used Twitter to raise awareness, such as the late Kate Granger's #hellomnynameis campaign. Tommy Whitelaw, a keynote speaker at this year's RCN congress in Glasgow, tweets under @TommyNtour to raise awareness of dementia by sharing his mother's story.


The Impact of COVID-19 on Neck of Femur Fracture Care: A Major Trauma Centre Experience, United Kingdom.
The aim of this study was to investigate the impact of the COVID-19 pandemic on the management and outcome of patients with neck of femur fractures. Data was collected for 96 patients with neck of femur fractures who presented to the emergency department between March 1, 2020 and May 15, 2020. This data set included information about their COVID-19 status. Parameters including inpatient complications, hospital quality measures, mortality rates, and training opportunities were compared between the COVID-19 positive and COVID-19 negative groups. Furthermore, our current cohort of patients were compared against a historical control group of 95 patients who presented with neck of femur fractures before the COVID-19 pandemic. Seven (7.3%) patients were confirmed COVID positive by RT-PCR testing. The COVID positive cohort, when compared to the COVID negative cohort, had higher rates of postoperative complications (71.4% vs 25.9%), increased length of stay (30.3 days vs 12 days) and quicker time to surgery (0.7 days vs 1.3 days).The 2020 cohort compared to the 2019 cohort, had an increased 30-day mortality rate (13.5% vs 4.2%), increased number of delayed cases (25% vs 11.8%) as well as reduced training opportunities for Orthopaedic trainees to perform the surgery (51.6% vs 22.8%). COVID-19 has had a profound impact on the care and outcome of neck of femur fracture patients during the pandemic with an increase in 30-day mortality rate. There were profound adverse effects on patient management pathways and outcomes while also affecting training opportunities.


Long-term outcomes of perineal rehabilitation.
Pelvic floor muscle training (PFMT) is classified with a level 1 evidence and a grade A recommendation, but long term effects have not been studied thoroughly. This study aims at assessing the long-term effectiveness of perineal rehabilitation on patients with mild prolapse and pure stress urinary incontinence (IUS) symptoms. Retrospective observational study on 49 patients examined at the beginning of the observation and 60 months after receiving biofeedback assisted PFMT. We created two groups. Group A: 27 women with mild symptoms of prolapse and pure mild IUS; Group B: 22 symptomatic patients postsurgery. We considered as therapeutic success a 50% general reduction of the symptoms experienced by the patients in terms of reduction of leakage episodes, number of pads used, strength and endurance of the pubococcygeus muscle and initial prolapse signs/symptoms. Group A (follow-up 60 months): Reduction of prolapse symptoms: cured/much improved: 65% (17 patients); worsened: 22.4% (6 patients); unchanged: 18.5% (5 patients); reduction of urinary symptoms: cured/much improved: 59.3% (16 patients); surgery: 40.7% (11 patients); group B (follow-up 60 months); cured: 55.5% (12 patients); much improved: 44% (10 patients). In conclusion, as for the treatment of menopausal patients with symptoms of mild disorders of the urinary/genital system, excellent results were reported in women underwent rehabilitation, as a first approach or after failed TVT-O.


Epistaxis and arterial ligation.
The management of severe epistaxis is discussed. Three groups of patients with severe epistaxis are studied retrospectively. The group which had early arterial ligation performed had a significantly reduced length of stay in hospital without increased risk. We conclude that early arterial ligation is the treatment of choice in severe epistaxis.